Pentobarbital (PB) is a commonly used central nervous system (CNS) depressant. However, its therapeutic use is complicated by diverse, and even dangerous, side effects. PB has sedative-hypnotic, anesthetic and anticonvulsive actions. PB also has a constellation of specific cellular effects. We have discerned three distinct influences: 1) depression of excitatory transmission, 2) enhancement of GABA action and 3) a direct GABA-mimetic effect. Preliminary data have led to the hypothesis to be tested in this proposal: that various cellular actions of PB may be differentially important for different aspects of the behavioral responses seen. We will proceed by comparing the cellular actions of PB with those of other prototypic drugs which share some, but not all, of the behavioral effects of PB. We will use in vitro model preparations noted particularly for the technical advantages they offer this project. Isolated spinal cord preparations make it possible to obtain quantitative data, rapidly. With sucrose gap recording we will examine common effects of a series of general anesthetics and correlate these with their relative anesthetic potencies in order to identify those effects of PB which are responsible for general anesthesia. To extend the analysis to mammalian brain regions where the drugs act to produce the behavior, considerable time will be spent characterizing PB effects in the rat hippocampal slice preparation. This preparation will enable us to study PB interactions with synaptic potentials with a degree of control not possible otherwise. We will look at: 1) intra-and extracellularly recorded EPSPs and axonal transmission, 2) PB interactions with calcium-mediated potentials and 3) IPSPs, both somatic and dendritic, especially to discover why PB induced the appearance of a depolarizing dendritic IPSP. We will also compare the relative sensitivities of dendritic and somatic GABA receptors to PB. Once the cellular actions of PB have been defined in the hippocampal slice, we will compare the actions of phenytoin (anticonvulsant), diazepam (anticonvulsive and sedative) and halothane (general anesthetic) to PB. Such a comparison should: 1) permit design of drugs having specific CNS actions and few side effects; and 2) further our understanding of factors which control neuronal excitability.